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Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization and in‐depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter‐gene with IC50 values as low as 200 and 11 × 10−9m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI‐tobramycin (Tob) combination against PA biofilms using a tailor‐made squalene‐derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32‐fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker‐mediated therapy against PA infections opening up avenues for preclinical development. [ABSTRACT FROM AUTHOR]

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self‐assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug‐loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16‐fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use. [ABSTRACT FROM AUTHOR]

When applied as the nanoparticle formulation the QSI potentiates biofilm eradication capabilities of tobramycin by at least 32-fold. In article number 2004369, Martin Empting and colleagues describe a new generation of dual-loaded nanoparticles enabling efficient eradication of I Pseudomonas aeruginosa i biofilms. [Extracted from the article]

Titelbild: Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections (Angew. Keywords: biofilms; drug delivery; Pseudomonas aeruginosa; quorum sensing inhibitors; tobramycin EN biofilms drug delivery Pseudomonas aeruginosa quorum sensing inhibitors tobramycin 10285 10285 1 06/17/20 20200622 NES 200622 B Der simultane Transport b von Tobramycin- und Alkylchinolon-Inhibitoren durch ein selbstorganisiertes Nanopartikelsystem basierend auf Squalenylhydrogensulfat (SqNPs) stellt eine optimale therapeutische Maßnahme gegen Biofilminfektionen mit I P. aeruginosa i dar. Biofilms, drug delivery, Pseudomonas aeruginosa, quorum sensing inhibitors, tobramycin. [Extracted from the article]